Over half of HF patients today have a preserved ejection fraction (HFpEF) and so we now turn our attention in HL61912 to HFpEF because of its growing prevalence, high mortality, exorbitant costs, poorly understood pathophysiology, and the lack of a proven treatment. Because there are no accepted HFpEF animal models, mechanistic human studies are needed to identify and understand the factors that contribute to this systemic, global process that results in profound exercise intolerance (EI). We present new data here that HFpEF patients manifest significant abnormalities in both cardiac and skeletal muscle high-energy phosphate (HEP) metabolism and propose to determine their relationship to EI and clinical HF symptoms as well as disease progression for the first time in HFpEF patients. This proposal will exploit three new state-of-the-art noninvasive tools developed by the investigators and not available elsewhere in the US to quantify a) myocardial energy metabolism and energetic reserve at rest, b) skeletal muscle energy metabolism with a newly developed skeletal muscle energetic fatigability test, and c) nitric oxide-mediated coronary endothelial function (CEF). The main premise of this work is that energetic abnormalities in cardiac and/or skeletal muscle, potentially worsened by abnormal endothelial function, contribute independently to the development of exercise intolerance and predict subsequent heart failure hospitalizations and cardiovascular deaths. Thus the new in vivo metabolic findings will be related to established, conventional clinical HF indices, diastolic function, biomarkers, and objective measures of exercise intolerance in both cross-sectional and longitudinal fashion (6 months). Moreover, we will determine whether abnormal cardiac and/or skeletal muscle energetics independently predict exercise intolerance and heart failure clinical outcomes over 2 years. A broad investigative approach is important because HFpEF pathophysiology is thought to involve several interrelated systems (including diastolic dysfunction, vascular/endothelial dysfunction, peripheral mechanisms, and impaired energetics). These unique physiologic studies of myocardial, skeletal and coronary vascular changes promise to guide new diagnostic/phenotyping approaches in HFpEF, uncover critical relationships and mechanisms in HFpEF, termed by experts as the number one unmet need in cardiovascular medicine today.